Early increased risk of myocardial infarction was reported recently in women with coronary artery disease (CAD) who were randomized to hormone therapy in a secondary prevention clinical trial. Increased matrix metalloproteinase (MMP) activity could promote coronary thrombosis by enzymatically digesting the fibrous caps of vulnerable atherosclerotic plaques. According, we determined whether estrogen administered to postmenopausal women affects MMP-9 (gelatinase B), which is expressed in human atherosclerotic plaques. Thirty-three postmenopausal women - 10 with angiographically defined CAD and 23 healthy subjects - participated in randomized, double-blind, crossover trials with conjugated equine estrogens (CEE) 0.625 mg or placebo daily, each for one month. MMP-9 levels in serum were measured by ELISA and by gelatin zymography. Plasminogen activator inhibitor type-1 (PAI-1) was measured in plasma by ELISA. Results: On placebo treatment, serum levels of MMP- 9 were higher in women with CAD than in healthy women (501+/-95 vs. 335+/-110 ng/mL, p=0.018). Compared with placebo treatment,levels of MMP-9 were higher on CEE treatment both in women with CAD (648+/-116 vs. 501+/-95 ng/mL, p=0.02) and in healthy women (435+/-142 vs. 335+/- 110 ng/mL, p=0.002). Gelatin zymography showed geater MMP-9 levels in serum from CEE treatment relative to placebo in 8 of 10 women with CAD and in 19 of 23 healthy women. PAI-1 was lowered by CEE in women with CAD (28.5+/-21.0 vs. 42.3+/-26.8 ng/mL, p=0.03), a response reviously shown to enhance the activity of plasmin, a principal activator of MMPs. We conclude that estrogen therapy increases serum MMP-9 in postmenopausal women, including those with CAD in whom basal levels are higher than those of healthy postmenopausal women. MMP-9 activation by plasmin in the arterial wall could digest fibrous caps of vulnerable atheromatous plaques, provoking thrombosis. - atherosclerosis, myocardial infarction, matrix metalloproteinses, estrogen, plasmin